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Welcome to the May 2016 IDP Subgroup Newsletter!

In this New and Notable issue of the newsletter we provide a wide variety of papers for your enjoyment: from stories of how mussels adhere themselves to marine surfaces to reports of how proteins purposefully evolve to be less than perfect. And incredibly, intrinsically disordered proteins (IDPs) are the central players in all of these stories! Papers were selected for review based on their novelty and perceived impact. Enjoy and we look forward to your feedback!

This paper from the Shea and Israelachvili laboratories incorporates surface force apparatus experiments and atomistic simulations to investigate surface interactions of bio-inspired underwater glues. Marine mussels secrete an adhesive solution to fasten themselves to marine surfaces through plaque formation. These adhesives contain mussel foot proteins (MFPs), proteins  which adhere to a variety of surfaces and so have an array of possible uses in medical applications. MFPs are intrinsically disordered proteins with an abundance of the catecholic amino acid dopa (DOPA). The authors have shown, through excellent agreement between simulation and experiment, that these MFP peptides exhibit a strong binding affinity to methyl terminated (hydrophobic) surfaces, through direct cathecol-mediated interactions with surface methyl groups, but a relatively weaker binding affinity to hydroxyl terminated (hydrophilic) surfaces. Of particular importance, this study reveals molecular mechanisms of wet adhesion of these DOPA containing peptides for a starting point of development of next generation underwater adhesives.

Dr. Joan-Emma Shea is a Professor at the Department of Chemistry and Biochemistry and the Department of Physics at the University of California Santa Barbara

Dr. Jacob Israelachvili is a Professor at the Department of Chemical Engineering and Materials Research Laboratory at the University of California Santa Barbara

The structural ensemble, and thus function, of IDPs is in part reliant on the fraction and distribution of charged residues in the primary sequence. To decode this primary sequence information into structural characteristics, the Pappu lab has established a parameter known as the kappa value. This value describes the mixing of positive and negative charges in the primary sequence of an IDP, with well mixed sequences having low kappa values and highly segregated sequences having high kappa values.

In this paper, Das et al report on the role of charge patterns in intrinsically disordered regions (IDR) for coupling signaling events in the transcription factor regulator p27Kip.  The signaling motifs of p27Kip are separated by an almost one hundred residue intrinsically disordered region (IDR).  Through in silico techniques and in vitro solution experiments, like SAXS and kinase assays, the authors identified that charge distribution plays an important role in signalling in p27kip and in global conformational properties of this IDR. Variant sequences of this large IDR region were designed with a spectrum of kappa values while maintaining the amino acid composition of the wild type IDR. Incredibly, the authors were able to design p27Kip variants with greater coupled phosphorylation efficiency than the wild-type protein, suggesting that perhaps nature has evolved for a less efficient signal propagation event. This result could speak to a greater phenomenon in IDP control of signalling events, with sequences in IDPs evolving for a certain level of efficiency in cellular environments rather than the highest levels of efficiency.

Dr. Rohit Pappu is a professor in the Department of Biomedical Engineering and Center for Biological Systems Engineering at Washington University in St. Louis MO.

Coexisting Liquid Phases Underlie Nucleolar Subcompartments

The nucleolus – the cell’s sub-nuclear center for ribosome biogenesis – displays two extremely interesting yet apparently confounding behaviors. Extensive imaging studies have demonstrated that the nucleolus contains (at least) three distinct regions, believed to be responsible for different stages of ribosome assembly and maturation. Simultaneously, the nucleolus has been demonstrated to behave as a liquid, undergoing fusion, wetting, and gravitational sedimentation in the absence of the nuclear actin network. How can can apparent liquid-like properties be reconciled with well-defined spatial organization?

Recent work by Feric & Vaidya et al. sought to answer this question using a combination of in vivo, in vitro, and in silico approaches to tease apart the physical chemistry that might underlie these observations. IDRs identified in several key proteins were shown to have distinct preferences for one another and for the solution environment, facilitating organized and predictable spatial assembly. Importantly, the interplay between ordered domains and these IDRs was crucial for the spatial assembly, despite the fact these ordered domains were unable to undergo phase separation in isolation. The authors demonstrate the underlying principles elucidated through this work using numerical simulations that reproduce the in vitro and in vivo data, as well as constructing a model system using water, Crisco oil and silicone oil that demonstrates similar spatial behaviour. The implications from this work are substantial: it seems likely - if not inevitable - that other membrane-less organelles will display similar spatial organization as a consequence of the relative miscibility of their constitutive protein components. Such organization affords the construction of specific sub-organelle “bioreactors” (sub-regions consisting of a specific protein composition), in principle giving cells a way to organize complex and potentially hazardous processes in a manner that reduces side-reactions and maximizes enzymatic efficiency.

Dr. Cliff Brangwynne is an assistant professor in the Department of Chemical and Biological Engineering at Princeton University, New Jersey.

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

This recent paper published in the Proceeding of the National Academy of Sciences by Raveh and coworkers proposes a novel mechanism for nucleoplasmatic transport.  The nuclear pore complex (NPC) is the sole mediator of traffic between the cell’s nucleus and cytoplasm. Large macromolecules are selectively transported across the NPC by binding to nuclear transport factors (TFs). These TFs, in turn, traverse the NPC by transiently interacting with intrinsically disordered phenylalanine (FG) repeat domains that line the pore of the NPC.

By using long-timescale molecular dynamics (MD) simulations the authors propose a slide-and-exchange mechanism in which the FG repeats rapidly transition between strongly interacting and weakly interacting states, providing for fast exchange between FG motifs and displacement along the NPC pore.  The proposed mechanism exemplifies how dynamic and transient, but highly specific protein-protein interactions, can be used for efficient transport along the NPC. In addition, the authors described in detail the effects of using two water models: TIP4P-Ew and TIP4P-D in the distribution of structured sampled by these IDPs during MD simulations. By comparing to NMR measurements, the authors observed that the TIP4P-D model seems more appropriate to describe the disordered FG repeats.


Dr. David Cowburn is a professor in the Department of Biochemistry in the Albert Einstein College of Medicine, New York
Dr. Andrey Sali is a professor in the Department of Bioengineering and Therapeutic Sciences at the University of California at San Francisco

Identification of Dynamic Modes in an Intrinsically Disordered Protein Using Temperature-Dependent NMR Relaxation 

In this paper from the Blackledge lab, the authors study the dynamics of IDP model systems by NMR spin relaxation to demonstrate just how powerful auto and cross-correlation spin relaxation rates can be in defining IDP dynamics across a milieu of timescales. NMR spin relaxation studies provide the unique opportunity to atomically characterize the conformational ensembles of IDPs. However, the timescales of dynamics processes of IDPs remains poorly understood. Here the authors identify three temporally separable relaxation modes, denoted fast, intermediate, and slow relaxation. Further analysis reveals that the three modes correlate with librational motion (fast, tens of picoseconds), local backbone conformation sampling (intermediate, 0.5-1.5 ns), and segmental motion (slow, 5-25 ns) of the IDP. The robustness of the analysis being confirmed, the authors were able to analyze up to 61 relaxation rates simultaneously per amino acid, assigning local activation energy for each process, and extend the study to three IDPs of differing lengths and content. This work provides detailed information of the dynamics of a model IDP and sheds light on the timescales of IDP dynamics.


Dr. Martin Blackledge is a group leader at the Institut de Biologie Structurale in France

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